Abstract

Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely preempted by sensitivity to the aversive effects of MA. The bidirectional selective breeding of mice for high (MAHDR) and low (MALDR) voluntary MA consumption has consistently demonstrated an inverse genetic relationship between MA consumption and MA-induced conditioned taste aversion (CTA). The progenitors of the selected lines were individuals from the reciprocal F2 intercross of the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. A quantitative trait locus (QTL) previously identified on mouse chromosome 10 in the selected lines accounts for greater than 50% of the genetically-determined difference in MA intake in the MA drinking (MADR) lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) for which MA is an agonist. Accumulating evidence suggests that Taar1 is a quantitative trait gene (QTG) for MA intake. The D2 progenitor strain has a polymorphism in Taar1, resulting in loss of function of TAAR1.

The overarching goal of this dissertation was to further explore the relationships between sensitivity to aversive effects of MA and MA consumption. The first aim focused on the role of Taar1 in MA consumption and sensitivity to MA-induced CTA. I found that MA drinking and sensitivity to MA-induced CTA corresponded with Taar1 genotype. The segregation of the B6 Taar1 allele in MALDR mice confirms the direction of allele influence predicted by the chromosome 10 QTL, and was dominant in its protective effect against MA intake. Mice homozygous for the non-functional D2 Taar1 allele showed significantly increased consumption over the heterozygous or B6 homozygous animals.

The second aim focused on physiological responses to MA that may impart greater sensitivity to MA-induced aversion. I hypothesized that high aversion and low intake would be genetically associated with greater sensitivity to the effects of MA on body temperature and on stress response. Additionally, I hypothesized that increasing stress axis activity while MA intake was being established would reduce MA intake in MAHDR mice. Increased hypothermic response and reduced hyperthermic response, as well as elevation of plasma corticosterone (CORT) following MA, corresponded with high sensitivity to MA-induced aversion and functional TAAR1. Furthermore, consumption of CORT in solution with MA decreased preference for MA in MAHDR mice. Therefore, hypothermia and elevated CORT response may be aversive effects of MA that contribute to limiting MA consumption.

The third aim of this dissertation was to investigate norepinephrine transporter (NET) and serotonin transporter (SERT) involvement in regulation of MA aversion. MAHDR mice have higher expression of nucleus accumbens (NAcc) NET and SERT than MALDR mice. I hypothesized that MALDR mice would be more sensitive to NET and SERT blockade-induced CTA. Additionally, I hypothesized that repeated blockade of NET or SERT would reduce sensitivity to MA-induced CTA through transporter system adaptations. SERT, but not NET, blockade induced CTA more quickly in MALDR than MAHDR mice, and slowed onset of MA-induced CTA. Therefore, SERT may mediate some sensitivity to aversive effects of MA in MALDR mice. In general, this dissertation presents data indicating that voluntary MA consumption is, in part, regulated by TAAR1 function. Furthermore, behavioral and physiological studies indicate that TAAR1 increases sensitivity to aversive effects of MA, and may thereby protect against MA use.